The mitochondrial succinate dehydrogenase complex controls the STAT3-IL-10 pathway in inflammatory macrophages

Area of Science:

• Immunology
• Cell Biology
• Mitochondrial Biology

Background:

• Macrophage functions are metabolically regulated, but the mitochondrial electron transport chain's role is understudied.
• The succinate dehydrogenase (SDH)/complex II (CII) is a key component of the ETC.

Purpose of the Study:

• To investigate the role of SDH/CII in macrophage respiration and effector responses.
• To elucidate the impact of SDH/CII deficiency on inflammatory cytokine production.

Main Methods:

• Utilized knockout macrophages lacking catalytic subunits Sdha and Sdhb.
• Stimulated macrophages with LPS to assess inflammatory responses.
• Analyzed HIF-1α stabilization, IL-1β and IL-10 production, Stat3 phosphorylation, and mitochondrial reactive oxygen species (mitoROS).

Main Results:

• Absence of Sdha and Sdhb impaired macrophage respiration and HIF-1α stabilization.
• Macrophage-specific deletion of Sdha/Sdhb inhibited LPS-induced IL-1β and IL-10 production.
• SDH/CII deficiency led to excessive mitoROS accumulation and inhibited Stat3 tyrosine phosphorylation.

Conclusions:

• SDH/CII is essential for macrophage effector responses, including cytokine production.
• Mitochondrial dysfunction, characterized by mitoROS accumulation, impacts inflammatory signaling pathways like Stat3 phosphorylation.